SUMMARY OF WORK:Restenosis is a late complication found in 40-50% of patients undergoing percutaneous transluminal coronary angioplasty (PTCA) for symptomatic coronary artery disease. Restenosis is characterized by neointimal proliferation, which results from vascular smooth muscle cell (VSMC) migration and proliferation, and late vascular remodeling involving vessel shrinkage and the accumulation of extracellular matrix protein. Coronary stents reduce the incidence of acute elastic recoil and late vascular remodeling following angioplasty, but remain vulnerable to restenosis because of in-stent neointimal hyperplasia. The hyperplastic response triggered by balloon injury is critically dependent on microtubules which are in dynamic equilibrium with their soluble protein constituents, alpha and beta tubulin. The antineoplastic drug, paclitaxel, inhibits microtubule function by shifting the equilibrium towards the polymerized state. We tested whether paclitaxel will prevent the microtubule-dependent processes involved in neointima formation by deploying paclitaxel- coated Palmaz-Schatz stents in the LAD coronary artery of NIH minipigs and monitoring the vascular response to injury using quantitative coronary angiography and histomorphometry. At 4 weeks post-injury, only the highest dose of paclitaxel (187 mcg/stent) produced a significant reduction in the angiographic late loss index (LLI) compared to control (p<0.002). These effects were consistent with the decrease in the neointimal area (0 vs 187 mcg/stent; p<0.05) and increase in the luminal area (0 vs 187 mcg/stent; p<0.003). There were no deaths from thrombotic complications; however, local effects of toxicity were apparent (focal hemorrhage, medial wall thinning, necrosis)and increased in severity with increasing drug dose. To assess long-term efficacy and safety, a 6 month testing program was established using an expanded range of paclitaxel concentrations bracketed by the intermediate (15 mcg/stent) and high doses (187 mcg/stent) from the 4 week study. Of the 50 pigs stented, only one died after 3 months of complications unrelated to thrombosis, aneurysm or rupture of the LAD. The 6 month dose-response relationship was biphasic for each of the indices tested (LLI, neointimal and luminal areas)with the largest reduction in neointimal hyperplasia occurring in the intermediate dose range (15-30 mcg/stent). The therapeutic effect disappeared at the highest dose tested because of neoinitmal regrowth involved in vessel repair. We conclude that paclitaxel satisfies the criteria for long- term safety and that intermediate range doses produce the optimum therapeutic effect. Studies are in progress to determine the length of time taken to re-establish the endothelial cell lining after exposure to paclitaxel. This information is crucial for determining how long patients should be maintained on anti-coagulant therapy following PTCA with paclitaxel-coated stents. - Restenosis, Paclitaxel, Porcine Model